This project investigates the relationship between genetic variation of human lipolytic enzymes and the development of hyperlipidemia and atherosclerosis in man. Genetic reduction of the lysosomal enzyme acid lipase, is associated with an increased incidence of hypercholesterolemia; family studies have revealed that inherited variants of acid lipase with reduced enzyme activity, segregate in some families selected on the basis of hypercholesterolemia. These findings will be extended to include our families, and we will attempt to uncover the role of acid lipase activity in modulating serum cholesterol levels. Another intracellular lipid hydrolyzing activity, neutral cholesteryl esterase, will be investigated in order to determine whether genetic variation of this enzyme occurs in man. If so, we will attempt to determine whether such variation is associated with predisposition to atherosclerosis. Because inherited variation of acid lipase is associated with rare inborn errors of metabolism (Wolman disease, cholesteryl ester storage disease) as well as with relatively common disorders (hyperlipidemias), we are also engaged in the search for genetic variation of other steps in lipid metabolism (e.g., lipid hydrolysis, uptake and esterification) associated with disease.